EFFECTS OF PARTIAL NEUROMUSCULAR BLOCKADE ON CAROTID BAROREFLEX FUNCTION DURING STATIC EXERCISE IN HUMANS

Concomitant increases in heart rate (HR) and mean arterialpressure (MAP) in response to physical activity have ledinvestigators to conclude that the arterial baroreflex iseither attenuated or not necessary during exercise (Bristowet al. 1971; McRitchie et al. 1976; Mancia et al. 1978).However, Melcher & Donald (1981) determined that duringexercise the carotid baroreflex maintained its sensitivity.In addition, they suggested that the operating point ofthe baroreflex was relocated upward on the response armof the baroreflex function curve in direct relation to theintensity of exercise. The relocation of the arterialbaroreflex would enable a coincident increase in bothHR and MAP. Subsequently, DiCarlo & Bishop (1992)demonstrated that the arterial baroreflex immediatelyresets at the start of exercise. Potts et al. (1993) haveprovided evidence that baroreflex function was maintainedduring exercise and was relocated upward on the responsearm and rightward to higher operating pressures (classicalresetting). Furthermore, this study described a relocationof the operating point away from the centring point and

closer to the threshold pressure region of the baroreflexfunction curve. These data suggested that baroreflexfunction was reset to operate around the prevailingexercise-induced blood pressure. In addition, the relocationof the operating point allowed the baroreflex to respondto a wider range of carotid sinus hypertension. It has beenconfirmed that the resetting of the carotid baroreflexoccurs in direct relation to the intensity of exercise (rest tomaximum exercise) (Papelier et al. 1994; Norton et al.1999) and that the resetting of the CBR occurs duringstatic exercise (Ebert, 1986).

Rowell & O’Leary (1990) presented a hypothetical schemesuggesting that two neural mechanisms were primarilyinvolved in the resetting of the carotid baroreflex duringexercise. They proposed that a feed-forward neuralmechanism (central command), which activates cardio-vascular and motor responses in parallel, was responsiblefor relocating the operating point of the carotidbaroreflex to higher arterial blood pressure (rightward)

Effects of partial neuromuscular blockade on carotidbaroreflex function during exercise in humans

K. M. Gallagher, P. J. Fadel, M. Strømstad *, K. Ide *, S. A. Smith,R. G. Querry, P. B. Raven and N. H. Secher *

Department of Integrative Physiology and Cardiovascular Research Institute, Universityof North Texas Health Science Center, Fort Worth, TX 76107, USA and *Copenhagen

Muscle Research Center, Department of Anaesthesia, Rigshospitalet University ofCopenhagen, Copenhagen, Denmark

(Received 22 June 2000; accepted after revision 1 February 2001)

1. This investigation was designed to determine the contribution of central command to theresetting of the carotid baroreflex during static and dynamic exercise in humans.

2. Thirteen subjects performed 3.5 min of static one-legged exercise (20 % maximal voluntarycontraction) and 7 min dynamic cycling (20 % maximal oxygen uptake) under two conditions:control (no intervention) and with partial neuromuscular blockade (to increase centralcommand influence) using Norcuron (curare). Carotid baroreflex function was determined atrest and during steady-state exercise using a rapid neck pressure/neck suction technique.Whole-body Norcuron was repeatedly administered to effectively reduce hand-grip strengthby approximately 50 % of control.

3. Partial neuromuscular blockade increased heart rate, mean arterial pressure, perceivedexertion, lactate concentration and plasma noradrenaline concentration during both static anddynamic exercise when compared to control (P < 0.05). No effect was seen at rest. Carotidbaroreflex resetting was augmented from control static and dynamic exercise by partialneuromuscular blockade without alterations in gain (P < 0.05). In addition, the operating pointof the reflex was relocated away from the centring point (i.e. closer to threshold) duringexercise by partial neuromuscular blockade (P < 0.05).

4. These findings suggest that central command actively resets the carotid baroreflex duringdynamic and static exercise.

Journal of Physiology (2001), 533.3, pp.861–87011290 861

during exercise. This would allow for the reflex to remainoperational despite the increased blood pressure thatoccurs with exercise. They also proposed that a negativefeedback mechanism originating in the exercising muscle(exercise pressor reflex) was involved in the resetting ofthe baroreflex. It was suggested that the exercise pressorreflex would activate sympathetic neural activityresulting in a vertical relocation of the operating point ofthe arterial baroreflex. Together, these two neuralmechanisms would result in the rightward and upwardresetting of the baroreflex during exercise.

Goodwin et al. (1972) have provided evidence that cardio-respiratory control was altered in direct relation to changesin central command during exercise. Furthermore, the useof neuromuscular blockade to activate central commandhas demonstrated increases in HR, arterial blood pressure(Gandevia et al. 1993; Pawelczyk et al. 1997) and musclesympathetic nerve activity (Victor et al. 1989). Norton etal. (1999) demonstrated that during prolonged steady-state exercise, carotid baroreflex resetting was directlyrelated to development of muscle fatigue. Theyhypothesised that since central command was known toinfluence somatomotor responses, their findings providedevidence of its possible involvement in the resetting ofthe carotid baroreflex during exercise. Iellamo et al.(1997) have confirmed that in humans subjects centralcommand and the exercise pressor reflex together wereinvolved in the resetting of the arterial baroreflex duringexercise. However, the influence of central commandalone on the resetting of the carotid baroreflex has yet tobe directly investigated.

This study attempted to increase central commandinfluence on cardiovascular variables during steady-statedynamic exercise and static exercise with partialneuromuscular blockade without altering the magnitudeof exercise pressor reflex input. The investigation wasdesigned to determine the role of central command in theresetting of the carotid baroreflex during static anddynamic exercise in humans.

METHODSSubjects

Eleven men and two women, with a mean age of 27.1 ± 1.1 years(± S.E.M.), height of 180.9 ± 1.9 cm, weight of 74.4 ± 1.7 kg andmaximum oxygen uptake (VO2,max) of 3.49 ± 0.2 l min_1, volunteeredto participate in this investigation. Each subject was informed of allaspects of the study and signed an informed consent approved by theMunicipal Ethical Committee of Copenhagen, Denmark. Allexperiments were performed in accordance with the Declaration ofHelsinki. All subjects were non-smokers, were not taking medicationand were asymptomatic for cardiovascular and respiratory disease.The subjects were asked to abstain from alcoholic beverages andexercise for 24 h and caffeinated beverages for 12 h prior to anysession.

Exercise

Each subject performed preliminary incremental work rate(30 W min_1) exercise on a cycle ergometer (modified Krogh) to

volitional fatigue for the determination of VO2,max. After the maximalexercise test, the subject was familiarised with the protocols forbaroreflex testing and static exercise. On a separate day, the subjectsperformed static and dynamic exercise with and without theadministration of whole-body curare (Norcuron; Organon Telemika).For both protocols the subjects were seated in a semi-recumbentposition on a hospital bed which supported the subjects’ upper body.The bed was modified to allow the subjects to perform one-leggedstatic knee extension from a 90 deg knee angle and two-legged cycling.Preceding any exercise, the subjects attempted three static kneeextensions to determine maximal voluntary contraction (MVC). Twobouts of control static knee extension at 20 % of MVC wereperformed for 3.5 min. The static exercise bouts were followed by a7 min dynamic exercise protocol at 20 % VO2,max. All exercise boutswere separated by a minimum of 30 min. After a minimum of 1 h thestatic and dynamic exercise bouts were repeated at the same absolute(20 % of control MVC and VO2,max) workloads after the whole-bodyadministration of Norcuron. Each exercise bout was preceded by a5 min collection period for resting baseline measurements.

Static knee extension was accomplished by placing a padded straparound the ankle of the subject’s dominant leg. Force was recorded bya strain gauge dynamometer calibrated prior to each trial with anaccurate sensitivity (model 540 DNH, The Netherlands). In order forthe subject to maintain the desired force, visual feedback of forceproduced was provided to the subject on a monitor. However, dueto the effect of Norcuron on vision, verbal feedback was also used tomaintain force during exercise following the administration ofcurare. For dynamic exercise, the cycle ergometer was adjusted foreach subject so that the knee angle at maximal leg extension wasconsistent for both tests. Subjects were requested to maintain a pedalcadence of 60 r.p.m. as dictated by a metronome and they wereinstructed to keep their entire upper body relaxed during all testing.

Norcuron (10 mg (10 ml)_1), a non-depolarizing neuromuscularblocking agent, was administered through venous access in the backof the hand. Prior to Norcuron administration, static handgrip MVCwas determined in arbitrary units. A bolus dose of Norcuron wasinjected followed by 10 ml of saline. Supplemental doses wereadministered until handgrip strength was reduced to 50 % of control.After the desired reduction in strength was achieved, the 5 min restcollection period was initiated followed by the exercise bout. Theinjections were repeated as required in order to maintain the targetedreduction in muscle strength. At all times an Ambu-E resuscitatorapparatus, neostigmine and atropine were available.

Measurements

Heart rate was monitored by a standard lead II electrocardiogram.Mean arterial pressure (MAP) was monitored by a Teflon catheter (20gauge) placed in the brachial artery of the non-dominant arm. TheMAP catheter was connected to a sterile disposable pressuretransducer (Baxter, Uden, The Netherlands) interfaced with apressure monitor (Danico Electronic-Dialogue 2000, Denmark). The zeroreference pressure was set at heart level. During each experiment theHR and arterial blood pressure (ABP; i.e. mean (MAP), systolic (SBP)and diastolic (DBP) blood pressures) were acquired using a beat-to-beat customized software data acquisition system interfaced with apersonnel computer. In addition, ratings of perceived exertion (RPE)were obtained during the last 30 s of static exercise and at the 4th and7th minute of dynamic exercise using the 6–20 Borg scale (Borg, 1982).

The subjects respired through a mouthpiece attached to a low-resistance turbine volume transducer (Pneumotach, MedGraphic) formeasurements of breath volumes, while gases were continuouslysampled from the mouthpiece for analysis of fractional concentrationsof O2, CO2 and N2 to determine O2 uptake (mass spectrometer model2001; Medical Graphics Corporation, St Paul, MN, USA). The systemwas calibrated before each test using known high-precision standard

K. M. Gallagher and others862 J. Physiol. 533.3

gases. Device input signals underwent analog-to-digital conversionfor on-line breath-by-breath determination. Standardized calculationsof metabolic data were corrected for ambient conditions.

Samples of arterial blood were obtained at rest and during the last30 s of exercise for determination of plasma catecholamines andlactate concentration. Blood was placed in tubes kept on icecontaining reduced glutathione and EGTA and centrifuged at 3000 gfor 5 min at 3 °C. The plasma fraction was stored at _20 °C for blindanalysis of noradrenaline (NA) and adrenaline (A). Samples wereassayed by a single isotope radioenzymatic method (Knigge et al.1990). Remaining syringe blood samples were used immediately forlactate determination (Lac TSI 2300; Yellow Springs Instrument Co.,Inc., OH, USA).

Carotid baroreflex (CBR) control of HR and MAP was assessed usinga neck pressure/neck suction (NP/NS) technique. Pressure stimuliwere applied through a cushioned malleable collar placed around theanterior 2/3 of the neck. The neck collar was modified from a designdescribed by Sprenkle et al. (1986). Due to the brevity of the exerciseprotocols, a NP/NS technique with a rapid ramping of pressure wasused. Twelve computer controlled pulsatile pressures ranging from+40 to _80 mmHg (40, 40, 40, 40, 20, 10, 0, _10, _20, _40, _60,_80) were generated by a variable pressure source and delivered tothe neck collar through large bore two-way solenoid valves (model8215B, Asco, Florham Park, NJ, USA). Between each pressure pulsethe neck chamber pressure was vented to atmospheric pressure. Thegenerated neck collar pressure was measured by a pressure transducer(model DP45, Validyne Engineering, Northridge, CA, USA). Thecomputer software gated the pressure pulses to occur 50 ms afterinitiation of the R-wave detected by ECG. The 50 ms delay allowedthe artificial pressure/suction to coincide with the arterial pressurewave at the carotid sinus. Each pulse was 500 ms in duration. TheNP/NS pulse train was conducted at end-expiratory breath hold toeliminate the confounding effects of respiratory sinus arrhythmia.The total duration of breath hold varied between 10 and 12 s. Sixsubjects were unable to maintain the end-expiratory breath holdthroughout the entire NP/NS pulse train during dynamic exercise.Therefore only seven subjects were included in the dynamic exercisedata. During static exercise, two trains of pressure pulses wereapplied after the second minute of exercise. Three to four trains ofpressure pulses were applied during dynamic exercise after the 4thminute of exercise. A minimum of 45 s of recovery was allottedbetween rapid pulse trains of NP/NS. Pulse trains of NP/NS werealso performed at rest before all exercise bouts.

Data and statistical analysis

The dependent variables HR and MAP were used to create either thecarotid–cardiac (CSP–HR) or carotid–vasomotor (CSP–MAP)stimulus–response function curves when plotted against theindependent variable of estimated carotid sinus pressure (CSP).These curves were individually fitted for each subject to a fourparameter logistic function described by Kent et al. (1972). Thisfunction incorporates the following equation:

HR or MAP = A1{1 + exp[A2(CSP _ A3)]}_1 + A4.

Carotid sinus pressure was calculated by subtracting the chamberpressure from the pre-stimulus MAP. Parameter A1 was the range ofresponse of the dependent variable (maximum–minimum), A2 wasthe gain coefficient, A3 was the CSP required to elicit equal pressorand depressor responses (centring point) and A4 was the minimumresponse of HR or MAP. Individual data were applied to this modelby a non-linear least-squares regression that predicts a curve of ‘bestfit’ for the data and minimizes the sum of squares error.

Several characteristic parameters are derived from the resultingmodel including the estimated threshold (CSPthr), saturation (CSPsat)

and maximal gain (Gmax) of the CSP–HR and CSP–MAP reflexes.Baroreceptor CSPthr and CSPsat were described as the minimum andmaximum CSPs, respectively, that elicited a reflex change in HR orMAP. For calculation of CSPthr and CSPsat, we applied equationsdescribed by Chen & Chang (1991): CSPthr = _2.0/A2 + A3 andCSPsat = 2.0/A2 + A3. They determined that these calculations ofCSPthr and CSPsat represent the CSP at which MAP or HR were within5 % of their maximal or minimal responses. The gains of the CSP–HRand CSP–MAP reflexes were derived from the first derivative of theKent logistic function, with the maximal gain being defined as thegain value located at the centring point (CP) of the reflex. Inaddition, the operating point (OP) was defined as the intersection ofthe pre-stimulus HR or MAP and CSP (i.e. resting MAP). Centringpoint minus the operating point (CP _ OP) was used to define therelocation of the OP away from the CP. Parameters for all subjectswithin an experimental condition were averaged to provide groupmean responses.

A two-way analysis of variance (ANOVA) with repeated measureswas employed to determine significant differences at rest andexercise between either static or dynamic exercise with or withoutcurare. Student-Newman-Keuls post hoc pairwise comparisons wereused to establish significant group mean differences. In addition,Student’s paired t test was used for individual comparisons. Data arepresented as mean values with standard errors (mean ± S.E.M.).Significance was set at P < 0.05. All analyses were conducted usingSigmaStat (Jandell Corp.).

RESULTSSelected physiological responses

Partial neuromuscular blockade with curare (Norcuron)reduced static handgrip strength 50–60 % during rest,static and dynamic exercise (Table 1). The subjectsreported that after partial neuromuscular blockade,increased effort was required to maintain the sameabsolute workload as control. This was reflected bysignificantly increased ratings of perceived exertion(RPE) during static and dynamic curare exercise ascompared to the control exercise condition (Table 1). Inaddition, HR and MAP were significantly elevated bycurare during static and dynamic exercise (Figs 1 and 2).The HR and MAP reached steady state without additionalelevations at the second minute of static exercise and atthe fourth minute of dynamic exercise during control andneuromuscular blockade. Plasma arterial noradrenalineand lactate concentrations were significantly increasedduring static and dynamic exercise with curare comparedwith control (Table 1). Heart rate, MAP, noradrenalineand lactate were unaffected by curare at rest. At thesame absolute work rate, oxygen uptake and plasmaadrenaline concentration were unaltered by curare at restand throughout exercise (Table 1).

Logistic parameters of carotid baroreflex

The stimulus–response relationships for baroreflex controlof HR (CSP–HR) and MAP (CSP–MAP) at rest and duringstatic and dynamic exercise are shown in Figs 3 and 4.The four logistic parameters describing carotid baroreflexcontrol of HR and MAP during static and dynamic exerciseare presented in Table 2. The centring point of the reflex(A3) was progressively relocated from rest during control

Carotid baroreflex during exerciseJ. Physiol. 533.3 863


Figure 1. HR and MAP during 3 min of staticexercise

Heart rate and mean arterial pressure responses atrest and during 3 min one-legged static exercise (20 %maximal voluntary contraction) with (1) and without(0) administration of curare (partial neuromuscularblockade). Values are means ± S.E.M. * Significantdifference between control and partial neuromuscularblockade exercise (P < 0.05).

Figure 2. HR and MAP during 7 min of dynamicexercise

Heart rate and mean arterial pressure responses atrest and during 7 min dynamic cycling exercise (20 %maximum oxygen uptake) with (1) and without (0)administration of curare (partial neuromuscularblockade). Values are means ± S.E.M. * Significantdifference between control and partial neuromuscularblockade exercise (P < 0.05).

Table 1. Selected physiological responses

RPE VO2Strength Lactate Noradrenaline Adrenaline

(l min_1) (%) (mmol l_1) (nmol l_1) (nmol l_1)

Control Rest — 0.332 ± 0.03 100 0.71 ± 0.09 1.25 ± 0.17 0.51 ± 0.15Static 12.9 ± 0.5 0.460 ± 0.04 — 0.78 ± 0.08 1.70 ± 0.22 0.89 ± 0.16Dynamic-1 10.2 ± 0.4 0.897 ± 0.04 — — — —Dynamic-2 10.7 ± 0.4 0.921 ± 0.04 — 0.68 ± 0.10 1.92 ± 0.25 0.67 ± 0.12

Curare Rest — 0.382 ± 0.02 45.9 ± 7.0† 0.79 ± 0.10 1.55 ± 0.18 0.66 ± 0.12Static 15.7 ± 0.6* 0.487 ± 0.03 46.8 ± 5.4† 1.14 ± 0.12* 2.36 ± 0.32* 0.88 ± 0.22Dynamic-1 16.4 ± 0.9* 1.013 ± 0.07 — — — —Dynamic-2 15.5 ± 0.7* 0.915 ± 0.06 46.1 ± 4.9† 1.04 ± 0.1* 2.82 ± 0.30* 0.99 ± 0.24

Values are means ± S.E.M. RPE, ratings of perceived exertion; VO2, oxygen uptake; Strength, grip strength

remaining after curare administration compared to control; Static (n = 13), static contraction at 3rdminute; Dynamic-1 (n = 7), dynamic cycling at 4th minute; Dynamic-2, dynamic cycling at 7th minute.* Significantly different from control exercise; † significantly different from resting condition; P < 0.05.

exercise and was significantly increased from rest andcontrol exercise during partial neuromuscular blockade.The minimal HR and MAP response (A4) was significantlyincreased during control exercise and was furtheraugmented by the administration of curare. The range ofHR and MAP responses (A1) and the gain coefficient (A2)were unaltered by exercise under control conditions andfollowing administration of curare.

Carotid baroreflex variables during static exercise

The calculated variables describing the CSP–HR andCSP–MAP stimulus–response curves during static exerciseare shown in Tables 3 and 4. The maximal gains of the HRand MAP responses were found to be unaltered from thatof rest by static exercise under control conditions andfollowing administration of curare. Threshold (CSPthr)and saturation (CSPsat) carotid sinus pressures forCSP–HR and CSP–MAP responses were relocated tohigher CSPs from that measured at rest during controlstatic exercise and were significantly increased fromcontrol exercise by partial neuromuscular blockade. Thedifference between CSPthr and CSPsat measured undercontrol conditions and following administration of curarewas only significant using an a priori paired t test. Thepre-stimulus (PS) HR and MAP were significantly increasedfrom rest by control static exercise and were furthersignificantly augmented by partial neuromuscularblockade. The relationship between the operating point(pre-stimulus CSP) and the centring point (A3) was notaltered by control static exercise, but exercise followingadministration of curare increased the distance betweenthe operating point and the centring point for CSP–HR,moving the operating point closer to the threshold of thereflex. The relationship between the operating point andthe centring point for CSP–MAP was unaltered by

exercise both under control conditions and followingadministration of curare. Collectively, the relocationupward on the response arm and rightward to higheroperating pressures of the CSP–HR and CSP–MAPstimulus–response curves suggested resetting of the CBRduring control exercise which was further augmented bypartial neuromuscular blockade or an increased centralcommand influence (Fig. 3).

Carotid baroreflex variables during dynamic exercise

The maximal gains of the HR and MAP responses wereunaltered by dynamic exercise under control conditionsand following administration of curare (Tables 3 and 4).Threshold (CSPthr) and saturation (CSPsat) carotid sinuspressures for CSP–HR and CSP–MAP responses wererelocated to higher carotid sinus pressures from thatmeasured at rest during control dynamic exercise and weresignificantly increased from control exercise pressures bypartial neuromuscular blockade. Pre-stimulus HR wassignificantly increased from rest by control dynamicexercise. The operating point (pre-stimulus CSP) ofCSP–HR was significantly shifted away from thecentring point (A3) of the reflex, moving closer tothreshold during control exercise; partial neuromuscularblockade had no additional effect. Pre-stimulus MAP wasnot altered by control exercise, but was significantlyelevated from control exercise by partial neuromuscularblockade. In addition, the relationship between theoperating point and the centring point for MAP was notaltered by control dynamic exercise, but exercisefollowing administration of curare significantly relocatedthe operating point away from the centring point, closerto the threshold of the reflex when compared to control.Collectively, the relocation upward on the response armand rightward to higher operating pressures of the


Table 2. Logistic model parameters describing carotid sinus baroreceptor reflex control of HRand MAP

A1 A2 A3 A4

Carotid–cardiac baroreflex (beats min_1) (mmHg) (beats min_1)Rest control 22.4 ± 2.0 0.19 ± 0.06 94.3 ± 3.1 51.5 ± 3.0Static control 23.6 ± 2.2 0.14 ± 0.01 103.2 ± 3.7 63.6 ± 4.4†Dynamic control 25.0 ± 1.8 0.18 ± 0.06 105.0 ± 3.1 65.9 ± 4.8†Rest curare 22.2 ± 2.1 0.17 ± 0.04 96.4 ± 3.2 54.8 ± 3.0Static curare 23.8 ± 2.5 0.11 ± 0.02 121.8 ± 4.6*† 68.3 ± 5.0*†Dynamic curare 22.3 ± 2.4 0.13 ± 0.02 127.3 ± 8.5*† 80.6 ± 11.0*†

Carotid–vasomotor baroreflex (mmHg) (mmHg) (mmHg)Rest control 20.4 ± 2.3 0.10 ± 0.01 86.6 ± 4.5 76.6 ± 2.6Static control 19.4 ± 1.9 0.09 ± 0.01 102.5 ± 3.3† 91.5 ± 2.0†Dynamic control 18.5 ± 0.5 0.09 ± 0.01 91.9 ± 5.3 81.0 ± 4.4†Rest curare 20.7 ± 1.7 0.08 ± 0.01 89.8 ± 4.2 84.1 ± 3.1*Static curare 21.1 ± 1.8 0.11 ± 0.03 111.5 ± 4.2*† 97.8 ± 3.6*†Dynamic curare 26.3 ± 3.5 0.11 ± 0.02 111.4 ± 9.3*† 89.6 ± 5.3*†

Values are means ± S.E.M. A1, range (maximum–minimum); A2, gain coefficient; A3, carotid sinus pressure(CSP) at midpoint (centring point); A4, minimal response. * Significantly different from control exercise;† significantly different from resting condition; P < 0.05.


Table 3. Derived variables describing the stimulus–response relationship for carotid baroreflexcontrol of heart rate

Control Curare ———————————————————— —————————————————————

Rest Static Dynamic Rest Static Dynamic

CSPthr (mmHg) 73.3 ± 4.0 84.7 ± 4.0 84.4 ± 4.7 77.7 ± 2.9 98.4 ± 5.9*† 107.5 ± 8.2*†CSPsat (mmHg) 113.0 ± 4.9 121.6 ± 4.1 125.8 ± 5.8 114.5 ± 4.4 143.3 ± 5.4*† 147.4 ± 9.6*†HRPS (beats min_1) 63.6 ± 4.1 77.1 ± 3.5† 89.3 ± 4.3† 67.6 ± 5.2 87.1 ± 7.7*† 103.0 ± 7.6*†CP _ OP (mmHg) 3.3 ± 3.2 3.1 ± 2.8 11.9 ± 2.0† 3.0 ± 2.4 6.8 ± 3.7 16.9 ± 6.4†Max. gain (beats min_1 mmHg_1) _1.15 ± 0.47 _0.82 ± 0.12 _1.0 ± 0.26 _0.74 ± 0.10 _0.72 ± 0.13 _0.72 ± 0.14

Values are means ± S.E.M. CSPthr, carotid sinus threshold pressure; CSPsat, carotid sinus saturationpressure; HRPS, pre-stimulus HR; CP _ OP, centring point of reflex (A3) minus operating point of reflex(pre-stimulus CSP); Max. gain, point of greatest slope (i.e. gain coefficient) on 1st derivative curve oflogistic function. * Significantly different from control exercise; † significantly different from restingcondition; P < 0.05.

Figure 3. Reflex responses in HR and MAPduring static exercise

Reflex responses in HR (carotid–cardiac) and MAP(carotid–vasomotor) after perturbations to carotidsinus baroreceptors at rest (0), during control static(20 % MVC) one-legged exercise (•) and during staticexercise after administration of curare (Norcuron) forpartial neuromuscular blockade (9). Data pointsrepresent means ± S.E.M. Lines represent mean fits ofdata from individual subjects. Arrows indicateoperating points. Curare–rest curves were notsignificantly different from control–rest curves andhave been omitted for clarity.

Figure 4. Reflex responses in HR and MAPduring dynamic exercise

Reflex responses in HR (carotid–cardiac) and MAP(carotid–vasomotor) after perturbations to carotidsinus baroreceptors at rest (0), during controldynamic (20 % MVC) cycling exercise (•) and duringdynamic exercise after administration of curare(Norcuron) for partial neuromuscular blockade (9).Data points represent means ± S.E.M. Lines representfits of data from individual subjects. Arrows indicateoperating points. Curare–rest curves were notsignificantly different from control–rest curves andhave been omitted for clarity.

stimulus–response curves for CSP–HR and CSP–MAPsuggest resetting of the CBR during control exercisewhich was augmented by partial neuromuscular blockadeor when central command was increased (Fig. 4).

DISCUSSIONThe carotid baroreflex resets during dynamic and staticexercise without alterations in sensitivity or maximalgain (Melcher & Donald, 1981; Ebert, 1986; DiCarlo &Bishop, 1992; Potts et al. 1993). In addition, the carotidbaroreflex continuously resets in direct relationship tothe intensity of exercise (Papelier et al. 1994; Norton et al.1999). Rowell & O’Leary (1990) hypothesized thatafferent neural signals from the exercise pressor reflexand efferent signals from central command combine toproduce carotid baroreflex resetting during exercise. Thepresent investigation was designed to selectively increasecentral command in order to determine its role in theresetting of the carotid baroreflex during dynamic andstatic exercise. We confirmed that the carotid baroreflexwas reset during both static and dynamic exercise. Themajor new finding from this study was that the carotidbaroreflex was further reset upward on the response armand rightward to higher operating pressures from controlexercise when central command was enhanced withoutalterations in gain. This response suggests that centralcommand actively contributes to the resetting of thecarotid baroreflex at the onset of static and dynamicexercise.

The cardiovascular responses to exercise are mediated inpart by central command input (Goodwin et al. 1972;Innes et al. 1992). Central command is a ‘feed-forward’controller that when activated has a diffuse outflow ofefferent communication from its putative location in thehypothalamic locomotor region. Central command activatesmultiple centres involved in the initiation of motoractivity (Waldrop et al. 1996) and is capable of initiatinglocomotion when stimulated (Waller, 1940). Additionally,locomotor region activation stimulates cardiovascular

control centres in the ventrolateral medulla and lateralreticular nucleus of the medulla (Nolan et al. 1992). Thusit is thought that central command involves a parallel,simultaneous excitation of neuronal circuits that elicitsmotor unit recruitment and adjusts cardiovascularactivity in a manner appropriate for the work (exercise)being performed (Waldrop et al. 1996). One model forindependently studying central command has utilizedpartial neuromuscular blockade (Leonard et al. 1985;Galbo et al. 1987; Victor et al. 1989, 1995; Pawelczyk et al.1997). Subjects exercising during partial neuromuscularblockade require increased motor unit recruitment tomaintain the same absolute work rates as during controlexercise. Therefore, since central command contributes tomotor unit recruitment, partial neuromuscular blockadewas hypothesized to augment central command (Mitchell,1990).

We used whole-body curare (Norcuron) to partially blockthe neuromuscular junction during exercise in order toincrease central command input. Each subject’s handgripstrength was reduced to 40–50 % of their control MVCduring partial neuromuscular blockade. Therefore, subjectsrequired an increase in effort, i.e. central command, inorder to maintain the same absolute work rates as duringcontrol exercise. This augmentation of central commandwas reflected by increased ratings of perceived exertion(RPE) during partial neuromuscular blockade. In addition,complementing previous work (Leonard et al. 1985;Pawelczyk et al. 1997), HR and MAP responses wereaugmented during partial neuromuscular blockade.Interestingly, oxygen uptake appeared to be unaffectedby partial neuromuscular blockade. Despite the increasedcentral effort needed to execute the work, the subjectswere still performing the same absolute amount of work.In other words, increased central command activatedadditional motor units, but due to the neuromuscularblockade, the same amount of muscle fibres were requiredto achieve the same absolute work rate. Therefore, it isapparent that, due to its effects on HR and RPE, partialneuromuscular blockade effectively augmented central


Table 4. Derived variables describing the stimulus–response relationship for carotid baroreflexcontrol of mean arterial pressure

Control Curare———————————————————————————————— ——————————————————————————————————

Rest Static Dynamic Rest Static Dynamic

CSPthr (mmHg) 65.9 ± 4.6 73.6 ± 6.3 68.3 ± 5.4 62.8 ± 4.4 83.7 ± 6.4*† 87.6 ± 12.5*†CSPsat (mmHg) 107.3 ± 5.1 131.4 ± 4.2† 115.5 ± 5.5 116.8 ± 5.6 139.3 ± 4.4*† 135.1 ± 7.5*†MAPPS (mmHg) 89.5 ± 2.1 99.7 ± 1.8† 91.7 ± 2.2 94.6 ± 2.5 111.5 ± 3.6*† 114.6 ± 6.5*†CP _ OP (mmHg) 0.34 ± 4.8 2.7 ± 2.9 5.7 ± 4.6 _3.0 ± 3.1 5.4 ± 3.0 16.3 ± 6.3*†Max. gain (mmHg min_1 mmHg_1) _0.51 ± 0.06 _0.38 ± 0.05 _0.41 ± 0.03 _0.41 ± 0.06 _0.49 ± 0.1 _0.63 ± 0.06

Values are means ± S.E.M. CSPthr, carotid sinus threshold pressure; CSPsat, carotid sinus saturationpressure; MAPPS, pre-stimulus MAP; CP _ OP, centring point of reflex (A3) minus operating point ofreflex (pre-stimulus CSP); Max. gain, point of greatest slope (i.e. gain coefficient) on 1st derivative curveof logistic function. * Significantly different from control exercise; † significantly different from restingcondition; P < 0.05.

command without increasing the work of the activemuscle, thereby maintaining the exercise pressor reflexinput constant between conditions.

A unique finding of the present investigation was thatpartial neuromuscular blockade significantly increasedblood lactate concentration above control exercise duringboth dynamic and static exercise protocols. Curareselectively inhibits slow-twitch muscle fibres resulting ina predominance of fast-twitch fibres remaining to performwork (Galbo et al. 1987). Activation of primarily fast-twitch muscle fibres would result in an augmentation ofglycolytic production of lactate. It is also possible thatactivation of the sympathetic nervous system by centralcommand may have stimulated the glycolytic pathway.However, the elevation of lactate values does raise thepossibility of activation of the exercise pressor reflex viastimulation of chemically sensitive metaboreceptors.

Activation of proposed locations for central commandoriginating in the motor cortex, insular cortex and theposterior hypothalamus (Bauer et al. 1988; Dillon et al.1991; Waldrop et al. 1996; Saleh & Connell, 1998) havedemonstrated alterations in baroreflex control of HR. Inaddition, medullary neurons that form the centralbaroreceptor pathway receive synaptic input from centralcommand (McMahon et al. 1992; Waldrop et al. 1996;Potts et al. 1998). Thus, central command input mayactively reset the carotid baroreflex by modulatingmedullary neuron pools that form the central baroreceptorpathway. During dynamic and static exercise in thepresent investigation, threshold and saturation carotidsinus pressures and the minimal response for thecarotid–cardiac and carotid–vasomotor baroreflex curveswere increased from rest during control exercise and weresignificantly elevated from control exercise by partialneuromuscular blockade. In addition, the centring pointof the responses (A3) was significantly raised by controlexercise and further significantly increased duringneuromuscular blockade. The maximal gains of the HRand MAP responses were found to be unaltered by eithercontrol or neuromuscular blockade exercise. These responsescoincide with Heesch & Carey’s (1987) description ofresetting of the carotid baroreflex as parallel increases insaturation and threshold without alterations in gain.Therefore, the carotid–cardiac and carotid–vasomotorstimulus–response curves were reset by control dynamicand static exercise and this resetting was furtheraugmented upward on the response arm and rightward tohigher operating pressures by neuromuscular blockade.The data of the present investigation suggest that centralcommand was actively involved in the classic upward andrightward resetting of the carotid baroreflex during bothdynamic and static exercise.

Potts et al. (1993) and Norton et al. (1999) report thatsteady-state HR and MAP (or CSP operating point) arerelocated away from the centring point and progressivelycloser to the threshold region of the stimulus–response

curve with each increment in dynamic exercise intensity.These findings suggest that a relocation of the operatingpoint permits the carotid baroreflex to respond to a widerrange of carotid sinus hypertension. We did notdemonstrate any shifts in the location of the operatingpoint on the baroreflex stimulus–response curves duringstatic and dynamic exercise, except for the HR responseto dynamic exercise. This was possibly due to the lowdynamic and static work rates used in the presentexperiment. However, relocation of the pre-stimulus HRand MAP away from the centring point and closer to thethreshold did occur during dynamic exercise followingneuromuscular blockade. Therefore, central commandappears to contribute to the relocation of the operatingpoint during exercise, as previously suggested (Potts et al.1993; Norton et al. 1999). This relocation may enable thecarotid baroreflex to respond to systemic hypertensionduring exercise with a greater range of responses, aconcept demonstrated by Sheriff et al. (1987) to provide afunctional brake on the exercise pressor reflex.

The findings of the present investigation by no meansexclude the involvement of the exercise pressor reflex inthe resetting of the carotid baroreflex during exercise.McWilliam et al. (1991) have clearly demonstrated inanimal studies that peripheral reflex mechanismscontribute to changes in the baroreceptor reflex duringmuscle contraction. The redundant nature of centralcommand input and the exercise pressor reflex in theregulation of the cardiovascular system is generallyaccepted (Mitchell, 1990). In addition, several studieshave provided evidence of vertical resetting of the carotidbaroreflex during exercise pressor reflex stimulation(Eiken et al. 1992; Shi et al. 1993, 1997; Papelier et al. 1997).Potts & Mitchell (1998) have demonstrated rightwardrelocation of threshold CSP with activation of skeletalmuscle afferents. Furthermore, medullary neurons thatform the central baroreceptor pathway receive synapticinput from skeletal muscle receptors (Kalia et al. 1981;Nyberg & Blomqvist, 1984; Waldrop et al. 1996). Thus, itappears that the exercise pressor reflex is involved in theresetting of the carotid baroreflex. Given the findings ofthe present study, we suggest that central command (afeed-forward mechanism) is the primary mediator ofcarotid baroreflex resetting at the onset and duringexercise. Further, the magnitude of resetting may bemodulated by exercise pressor reflex input (a feedbackmechanism) in response to mechanical and metabolicdemands placed on active muscle.

In summary, we have confirmed that the stimulus–response relationship of the carotid baroreflex is resetduring dynamic and static exercise to the prevailingsystemic pressure. We also demonstrated that increasedcentral command further resets the carotid baroreflexupward on the response arm and rightward to higheroperating pressures (classical resetting) in the samemanner during dynamic and static exercise without


altering the gain of the reflex. In addition, we found thatincreased central command relocated the pre-stimulusHR and MAP, i.e. the operating point, away from thecentring point and closer to the threshold of the reflexduring exercise. We conclude that central command isactively involved in the ‘classical resetting’ of the carotidbaroreflex that occurs between rest and the onset ofexercise. Furthermore, the degree of resetting of thebaroreflex is directly related to the intensity of theexercise which is commensurate with the magnitude ofcentral command activation.

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Acknowledgements

The authors would like to thank Kasper Horn for his technicalsupport and Lisa Marquez for secretarial support during thepreparation of the manuscript. This study was supported by theDanish National Research Foundation Grant (504-14) from theCopenhagen Muscle Research Center, Copenhagen, Denmark. Thispaper was submitted by K. M. Gallagher to the University of NorthTexas Health Science Center at Fort Worth in partial fulfillment ofthe requirements for the degree of Doctor of Philosophy.

Corresponding author

P. B. Raven: Department of Integrative Physiology, University ofNorth Texas Health Science Center, 3500 Camp Bowie Boulevard,Fort Worth, TX 76107-2699, USA.

Email: [email protected]


EFFECTS OF PARTIAL NEUROMUSCULAR BLOCKADE ON CAROTID BAROREFLEX FUNCTION DURING STATIC EXERCISE IN HUMANS

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